Project Summary/Abstract Lyme disease, caused by the tick transmitted pathogen Borrelia burgdorferi, is estimated to be responsible for 300,000 new cases per year in the United States. Disease manifestations include a skin lesion at the site of the tick bite, followed by disseminated symptoms including secondary skin lesions, arthritis, Bell?s palsy, peripheral neuropathies, meningitis/encephalitis, and carditis. Most individuals respond to antibiotic treatment, particularly if started early in infection, however, up to 20% of patients experience a delay in the return to normal health. This persistence of symptoms following antibiotic treatment is termed post treatment Lyme disease symptoms, PTLDS, and encompasses disseminated symptoms including neurological abnormalities, fatigue, and arthritis. The underlying mechanism of sustained symptoms is not understood and is an area of active investigation. Hypotheses include presence of persister spirochetes, presence of pro-inflammatory bacterial fragments, dysregulation of anti-inflammatory processes, and emergence of auto-reactive B and T lymphocytes. The lack of easily manipulated animal model has limited understanding of chronic disease. Using the IL-10 deficient mouse as a model for joint disease that persists following immune-mediated clearance of B. burgdorferi, we have identified bystander activation of T lymphocytes that drive IFN dependent arthritis. Bystander activation of T cells is independent of classic MHC-TCR engagement, but dependent on T cell intrinsic expression of TLR2. We have also found that patients with PTLDS have elevated numbers of activated CD4+ and CD8+ T cells in their peripheral blood, when compared with patients who return to normal health. We will expand molecular characterization of bystander-activated T cells in mice and patients in order to identify novel targets for therapeutic intervention. These will be tested in the IL-10-/- model of chronic Lyme disease. Preliminary studies indicate short-term targeting of TLR2 is potential therapeutic for Lyme arthritis. The overall goal of study is to identify novel treatments for chronic Lyme disease that target inappropriately activated T cells without compromising host defense.